Transient receptor potential (TRP) channels are one of the largest groups of ion channels, and they are divided into 6 sub-families (TRPV, TRPM, TRPA, TRPC, TRPP and TRPML). TRP channels are cation-selecive channels that are activated by a variety of physical (e.g., temperature, osmolarity, mechanical) and chemical stimuli. TRPM8 is a member of TRP channel family. The receptor was cloned in 2002 (NPL 1; NPL 2) and it was found to be sensitive to cold temperature and menthol, and therefore named as cold menthol receptor-1 (CMR-1). TRPM8 can sense temperature changes in the range of both innocuous cold (15-28° C.) and noxious cold (<15° C.) as well as by chemical agents such as menthol and icilin.
TRPM8 is located on primary nociceptive neurons including A-delta and C-fibers and is also modulated by inflammation-mediated second messenger signals (NPL 3; NPL 4). The localization of TRPM8 on both A-delta and C-fibers may provide a basis for abnormal cold sensitivity in pathologic conditions wherein these neurons are altered, resulting in pain, often of a burning nature (NPL 5; NPL 6; NPL 7, NPL 8, NPL 9). Gauchan et al. reported that the expression of TRPM8 in the primary afferents was increased in oxaliplatin-induced cold allodynia model in mice (NPL 10). Oxaliplatin, a third-generation platinum-based chemotherapy drug, induces serious sensory neurotoxicity in patients, which is aggravated by exposure to cold. Recently, Glenmark group reported that the small molecular TRPM8 antagonists produced a dose-dependent inhibition of nocifensive paw licking in oxaliplatin-induced cold allodynia in mice (NPL 11).
Cold intolerance and paradoxical burning sensations induced by chemical or thermal cooling closely parallel symptoms seen in a wide range of clinical disorders and thus provide a strong rationale for the development of TRPM8 modulators as novel antihyperalgesic or antiallodynic agents. TRPM8 is also known to be expressed in the brain, odontoblasts, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells, thereby providing the possibility for therapeutic modulation in a wide range of maladies.
International patent application WO 2006/040136 (PTL 1) purportedly describes substituted 4-benzyloxy-phenylmethylamide derivatives as cold menthol receptor-1 (CMR-1) antagonists for the treatment of urological disorders. International patent application WO 2006/040103 (PTL 2) purportedly describes methods and pharmaceutical compositions for treatment and/or prophylaxis of respiratory diseases or disorders. Recently, International patent application WO 2014/025651 (PTL 3) from Amgen Inc. purportedly describes chroman compounds and derivatives as TRPM8 inhibitors for the treatment of migraines and neuropathic pain.
The compounds of the present invention which have TRPM8 receptor antagonist activity are structurally quite different from prior arts.
WO 2010/037081 (PTL 4) and US005739336A (PTL 5) disclose spiropiperidine derivatives. However, the chemical structures of the compounds disclosed in the both patents are quite different from the compounds of the present invention. In addition, the compounds disclosed in the both patents relate to melanocortin receptor inhibitors and selective 5HT2c receptor antagonists, respectively, which is quite different from TRPM8 receptor antagonist.
WO 2012/174342 (PTL 6) and WO 2011/148962 (PTL 7) disclose spiro[cyclohexane-oxazolidinone] derivatives. However, the chemical structures of the compounds disclosed in the both patents are quite different from the compounds of the present invention. In addition, the compounds disclosed in the both patents relate to TRPV4 antagonists and antibacterial agents, respectively, which is quite different from TRPM8 receptor antagonist. The invention in WO 2005/044978 (PTL 8) discloses spiro derivatives which relate an activated α1|bβ3 (alpha1|bbeta3) receptor antagonist, is different from the present invention in the both aspects of chemical structures and biological activities.
Therefore the azaspiro derivatives in the present invention which have TRPM8 receptor antagonist activity have never been disclosed in prior arts.